Spinal muscular atrophy (SMA) is a fatal genetic disease. It is caused by mutations in the Survival of Motor Neuron (SMN) gene and is the second most common genetic cause of childhood mortality [6]. It is characterized by progressive symmetrical limb and trunk paralysis and muscular atrophy. Currently, there are no therapies for SMA patients, because little is known about the function of SMN and the pathobiology of the disease, except that it affects motor neurons (MNs). Although the SMN protein is expressed in many tissues, including nervous and non-nervous tissues, MNs appear to be most affected in SMA. It is not known what role SMN plays in causing SMA pathology and how deletion or mutation of SMN may lead to selective MN vulnerability. Pathology in MNs may be related to subcellular mislocalization, lack of function, or aberrant function. Alternatively, MN injury may b a secondary result of skeletal muscle or musculoskeletal pathology that causes neuromuscular junction abnormalities. It remains unclear whether the initiating insult is in neurons or muscle, and it is unknown whether other organ systems are affected. The ultimate goal of the project described here will be to suggest therapeutic approaches targeting specific degenerative pathways. This goal will be achieved by two specific aims. The first aim is to profile cell death proteins in spinal cord MNs and in skeletal muscle from a mouse model of SMA and from human SMA patients, in order to develop an adjuvant therapy for SMA distinct from SMN reconstitution. This aim will test the hypothesis that apoptosis is the mechanism for degeneration in SMA and define the specific apoptotic pathways involved. Once a specific pathway is identified, it will be pharmaceutically inhibited in SMA mice to determine whether this can slow or prevent disease progression. The second aim is to test the hypothesis that the musculoskeletal system fails to develop properly in SMA mice, and that this musculoskeletal pathology is a primary insult, related to the inability of abnormal SMN to facilitate repair of DNA double strand breaks by homologous recombination in proliferating myoblasts, rather than a secondary consequence of motor neuron disease. This aim will be accomplished by examining, histologically and biochemically, spinal cord MN and skeletal muscle pathology in embryonic and neonatal SMA mice and in human SMA autopsy tissues. PUBLIC HEALTH RELEVANCE: Spinal muscular atrophy (SMA) is the second most lethal recessive genetic childhood disease. There are no cures and no effective treatments for SMA, in large part because it is not understood how the loss of the SMN gene leads to SMA. We will investigate the molecular and cellular mechanisms which cause motor neuron cell death and muscle atrophy in SMA, in order to identify therapeutic targets for this and other neurodegenerative disorders.